The intertwined epidemics of obesity and diabetes have produced a public health crisis that demands an improved understanding of fat biology and metabolism. Through genetic screens in C. elegans and D. melanogaster, we identified many genetic regulators of invertebrate fat storage/metabolism that also have a conserved role in mammals. We focused our attention on one gene, Adipose (Adp), because its striking anti-obesity and anti-diabetes function in worms, flies, and mammals highlight its importance in metabolism and potential as a therapeutic target. The goal of this proposal is to unravel the physiological and molecular mechanisms underlying these striking effects. Adp regulates an ancient metabolic pathway. Reducing Adp function in worms, flies, mammalian adipogenic cells, and mice stimulates fat formation (obesity) and Adp mutant flies and mice have diabetes. These effects result from actions of Adp within adipocytes, as adipocyte-restricted expression of dominant negative Adp in mice caused obesity and diabetes. Conversely, fat selective expression of wild-type Adp produces lean, glucose sensitive flies and mice. Yet, there remain several unexplored issues relating to the in vivo metabolic phenotypes. We propose to fill these gaps through detailed analyses of mice with altered Adp levels;initial studies indicate altered energy expenditure. We will also examine how Adp regulates the metabolic responses to diet-induced obesity (DIO), a major contributor to the current obesity-diabetes epidemics. Mechanistically Adp elicits anti-obesity functions by regulating chromatin dynamics and gene transcription. Adp binds histones, HDAC3, and Med23, a component of the Mediator complex. Our Preliminary Data indicate that Adp may act as a substrate receptor for the Cul4 ubiquitin ligase, thereby conferring target specificity to Cul4 action. Based upon these data, we will test the hypothesis that Adp controls gene expression by connecting Adp interacting proteins (AIPs;e.g., HDAC3, Med23, etc.) to the Cul4 complex thereby altering their ubiquitination/stability. Our hope is that these metabolic and molecular studies will enhance our understanding of mammalian metabolism and lead to novel therapeutic strategies for obesity and diabetes.